The fms-like tyrosine kinase 3 (FLT3) ligand (FLT3L) is one of the cytokines that affects the development of multiple hematopoietic lineages. These effects occur through the binding of FLT3L to the FLT3 receptor, also referred to as fetal liver kinase-2 (flk-2) and STK-1, a receptor tyrosine kinase (RTK) expressed on hematopoietic stem and progenitor cells. The FLT3 gene encodes a membrane-spanning class III RTK that plays an important role in proliferation, differentiation and apoptosis of cells during normal hematopoiesis. The FLT3 gene is mainly expressed by early myeloid and lymphoid progenitor cells. See McKenna, Hilary J. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood. June 2000; 95: 3489-3497; Drexler, H. G. and H. (2004). “FLT3: receptor and ligand.” Growth Factors 22(2): 71-3.
The ligand for FLT3 is expressed by the marrow stromal cells and other cells and synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells.
Hematopoietic disorders are pre-malignant disorders of these systems and include, for instance, the myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), angiogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF), polycythemia vera (PV), the cytopenias, and pre-malignant myelodysplastic syndromes. See Stirewalt, D. L. and J. P. Radich (2003). “The role of FLT3 in haematopoietic malignancies.” Nat Rev Cancer 3(9): 650-65; Scheijen, B. and J. D. Griffin (2002). “Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease.” Oncogene 21(21): 3314-33.
Hematological malignancies are cancers of the body's blood forming and immune systems, the bone marrow and lymphatic tissues. Whereas in normal bone marrow, FLT3 expression is restricted to early progenitor cells, in hematological malignancies, FLT3 is expressed at high levels or FLT3 mutations cause an uncontrolled induction of the FLT3 receptor and downstream molecular pathway, possibly Ras activation. Hematological malignancies include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma—for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), multiple myeloma, (MM) and myeloid sarcoma. See Kottaridis, P. D., R. E. Gale, et al. (2003). “Flt3 mutations and leukaemia.” Br J Haematol 122(4): 523-38. Myeloid sarcoma is also associated with FLT3 mutations. See Ansari-Lari, Ali et al. FLT3 mutations in myeloid sarcoma. British Journal of Haematology. 2004 Sep. 126(6):785-91.
Acute Myelogenous Leukemia (AML) is the most prevalent form of adult leukemia and represents 15-20% of childhood leukemias. In 2002, in the United States, approximately 11,000 new cases of AML were diagnosed and an estimated 8,000 patients died from AML. See National Cancer Institute SEER database—http://seer.cancer.gov/. Although diagnosis for AML is traditionally based on histological techniques and blood leukocyte count, recent advances in cytogenetic and genetic analysis have revealed that AML is a mixture of distinct diseases that differ in their genetic abnormalities, clinical features and response to therapy. Recent efforts have begun to tailor chemotherapy to the different sub-types of AML (subtypes are based on cytogenetic analysis and immunohistochemical analysis for disease associated protein expression) with some success. Treatment of AML typically occurs in two phases: induction and post-induction therapy. Induction therapy typically consists of three doses of an anthracycline such as daunorubicin followed by i.v. bolus infusion of the cytotoxic cytarabine for 7-10 days. This regime is effective at inducing remission in 70-80% of patient <60 years of age and 50% of patients >60. See Burnett, A. K. (2002). “Acute myeloid leukemia: treatment of adults under 60 years.” Rev Clin Exp Hematol 6(1): 26-45; Buchner T., W. Hiddemann, et al. (2002). “Acute myeloid leukemia: treatment over 60.” Rev Clin Exp Hematol. 6(1):46-59. After remission induction there are several post-induction options including an additional cycle of chemotherapy or bone marrow transplantation. Post-induction treatment choice and success depends on the patient's age and AML sub-type. Despite the advances in diagnosis and treatment of AML over the last decade, the 5 year disease free survival for patients under 65 is only 40% and the 5 year disease free survival of patients over 65 is less than 10% percent. Thus, there remains a significant unmet clinical need for AML particularly in patients over 65. With the increased knowledge of the mechanisms of the different sub-types of AML new tailored treatments for the disease are beginning to immerge with some promising results.
One recent success in relapse and refractory AML treatment is the development and use of farnesyl transferase inhibitors (FTI) for post-induction treatment. Farnesyl transferase inhibitors are a potent and selective class of inhibitors of intracellular farnesyl protein transferase (FPT). FPT catalyses the lipid modification of a host of intracellular proteins, including the small GTPases of the Ras and Rho family and lamin proteins, to direct their localization to the plasma membrane or membrane compartments within the cell.
FTIs were originally developed to prevent post-translational farnesylation and activation of Ras oncoproteins (Prendergast G. C. and Rane, N. (2001) “Farnesyl Transferase Inhibitors: Mechanism and Applications” Expert Opin Investig Drugs. 10(12):2105-16). Recent studies also demonstrate FTI induced inhibition of Nf-κB activation leading to increased sensitivity to induction of apoptosis and downregulation of inflammatory gene expression through suppression of Ras-dependent Nf-κB activation. See Takada, Y., et al. (2004). “Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappaB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappaB-regulated gene expression and up-regulation of apoptosis.” J Biol Chem 279, 26287-99.
Of particular interest for oncology, FTI inhibition of the oncogenes of the Ras and Rho family leads to growth arrest and apoptosis of tumor cells both in vitro and in vivo. See Haluska P., G. K. Dy, A. A. Adjei. (2002) “Farnesyl transferase inhibitors as anticancer agents.” Eur J Cancer. 38(13):1685-700. From a clinical perspective, myeloid malignancies, particularly AML, represent a significant opportunity for FTI therapy.
As discussed earlier, AML is a disease with very low long-term survival and an elevated rate of chemotherapy-induced toxicity and resistance (particularly in patients >60 years of age). Additionally, the mechanism of proliferation of AML cells relies on the small GTPases of the Ras and Rho family. With the plethora of pre-clinical data supporting the efficacy of FTIs in AML treatment, several clinical trials were initiated with an FTI including; R115777 (Zarnestra, Johnson and Johnson), BMS-214662, CP-60974 (Pfizer) and Sch-6636 (Ionafarnib, Schering-Plough).
ZARNESTRA® (also known as R115777 or tipifarnib) is the most advanced and promising of the FTI class of compounds. In clinical studies of patients with relapsed and refractory AML, Zarnestra treatment resulted in a ˜30% response rate with 2 patients achieving complete remission. See Lancet J. E., J. D. Rosenblatt, J. E. Karp. (2003) “Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias.” Semin Hematol. 39(3 Suppl 2):31-5. These responses occurred independently of the patients Ras mutational status, as none of the patients in the trial had the Ras mutations that are sometimes seen in AML patients. However, there was a direct correlation of patient responses to their level of MAPkinase activation (a downstream target of both Ras and Rho protein activity) at the onset of treatment, suggesting that the activity of the Ras/MAPkinase pathway, activated by other mechanisms may be a good predictor of patient responses. See Lancet J. E., J. D. Rosenblatt, J. E. Karp. (2003) “Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias.” Semin Hematol. 39(3 Suppl 2): 31-5. Additionally, a recent multicenter Phase II trial in patients with relapsed AML demonstrated complete responses (bone marrow blasts <5%) in 17 of 50 patients and a >50% reduction in bone marrow blasts in 31 of 50 patients. Reviewed in Gotlib, J (2005) “Farnesyltransferase inhibitor therapy in acute myelogenous leukemia.” Curr. Hematol. Rep.; 4(1):77-84. Preliminary analysis of genes regulated by the FTI treatment in responders in that trial also demonstrated an effect on proteins in the MAPKinase pathway. This promising result has experts in the field anticipating the use of Zarnestra in the clinic in the near future.
Recently, another target for the treatment of AML, and a subset of patients with MDS and ALL, has emerged. The receptor tyrosine kinase, FLT3 and mutations of FLT3, have been identified as key player in the progression of AML. A summary of the many studies linking FLT3 activity to disease have been extensively reviewed by Gilliland, D. G. and J. D. Griffin (2002). “The roles of FLT3 in hematopoiesis and leukemia.” Blood 100(5): 1532-42, and Stirewalt, D. L. and J. P. Radich (2003). “The role of FLT3 in haematopoietic malignancies.” Nat Rev Cancer 3(9): 650-65. Greater than 90% of patients with AML have FLT3 expression in blast cells. It is now known that roughly 30-40% of patients with AML have an activating mutation of FLT3, making FLT3 mutations the most common mutation in patients with AML. There are two known types of activating mutations of FLT3. One is a duplication of 4-40 amino acids in the juxtamembrane region (ITD mutation) of the receptor (25-30% of patients) and the other is a point mutation in the kinase domain (5-7% of patients). These receptor mutations cause constitutive activation of multiple signal transduction pathways including Ras/MAPkinase, PI3kinase/AKT, and the STAT pathways. Additionally, the FLT3ITD mutation also has been shown to decrease the differentiation of early myeloid cells. More significantly, patients with the ITD mutation have decreased rates of remission induction, decreased remission times, and poorer overall prognosis. FLT3ITD mutations have also been found in ALL with the MLL gene rearrangement and in a sub-population of MDS patients. The presence of the FLT3ITD mutation in MDS and ALL is also correlated with accelerated disease progression and poorer prognosis in these patients. See Shih L. Y. et al., (2004) “Internal tandem duplication of fins-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome.” Cancer, 101; 989-98; and Armstrong, S. A. et al., (2004) “FLT3 mutations in childhood acute lymphoblastic leukemia.” Blood. 103: 3544-6. To date, there is no strong evidence that suggests either the kinase domain point mutations or the over expressed wild-type receptor is causative of disease, however, FLT3 expression may contribute to the progression of the disease. This building pre-clinical and clinical evidence has led to the development of a number of FLT3 inhibitors which are currently being evaluated in the pre-clinical and clinical setting.
An emerging strategy for the treatment of AML is the combination of target directed therapeutic agents together or with conventional cytotoxic agents during induction and/or post-induction therapy. Recent proof of concept data has been published that demonstrate the combination of the cytotoxic agents (such as cytarabine or daunorubicin) and FLT3 inhibitors inhibit the growth of AML cells expressing FLT3ITD. See Levis, M., R. Pham, et al. (2004). “In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects.” Blood 104(4): 1145-50, and Yee K W, Schittenhelm M, O'Farrell A M, Town A R, McGreevey L, Bainbridge T, Chemington J M, Heinrich M C. (2004) “Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3ITD-positive leukemic cells.” Blood. 104(13):4202-9.
Accordingly, the present invention provides a synergistic method of treatment comprising co-administration (simultaneous or sequential) of a novel FLT3 kinase inhibitor described herein and a farnesyl transferase inhibitor for the treatment of FLT3 expressing cell proliferative disorders.
A variety of FTase inhibitors are currently known. FTIs appropriate for use in the present invention are the following: WO-97/21701 and U.S. Pat. No. 6,037,350, which are incorporated herein in their entirety, describe the preparation, formulation and pharmaceutical properties of certain farnesyl transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond;    X is oxygen or sulfur;    R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,            or a radical of formula -Alk1—C(═O)—R9, -Alk1-S(O)—R9 or -Alk1-S(O)2—R9, wherein Alk1 is C1-6alkanediyl,                    R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;                            R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or            when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula—O—CH2—O—  (a-1),—O—CH2—CH2—O—  (a-2),—O—CH═CH—  (a-3),—O—CH2—CH2—  (a-4),—O—CH2—CH2—CH2—  (a-5), or—CH═CH—CH═CH—  (a-6);            R4 and R5 each independently are hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;    R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar2oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or            when on adjacent positions R6 and R7 taken together may form a bivalent radical of formula—O—CH2—O—  (c-1), or—CH═CH—CH═CH—  (c-2);            R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula—O—R10  (b-1),—S—R10  (b-2),—N—R11R12  (b-3),            wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk2-OR13 or -Alk2-NR14R15;                    R11 is hydrogen, C1-12alkyl, Ar1 or Ar2C1-6alkyl;            R12 is hydrogen, C1-6alkyl, C1-16alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, a natural amino acid, Ar1carbonyl, Ar2C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical of formula -Alk2-OR13 or -Alk2-NR14R15;                        wherein Alk2 is C1-6alkanediyl;                    R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar2C1-6alkyl;            R14 is hydrogen, C1-6alkyl, Ar1 or Ar2C1-6alkyl;            R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar2C1-6alkyl;                            R17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar1;    R18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;    R19 is hydrogen or C1-6alkyl;    Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and    Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
WO-97/16443 and U.S. Pat. No. 5,968,952, which are incorporated herein in their entirety, describe the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, whereinthe dotted line represents an optional bond;    X is oxygen or sulfur;    R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,            or a radical of formula -Alk1—C(═O)—R9, -Alk1-S(O)—R9 or -Alk1-S(O)2—R9,        wherein Alk1 is C1-6alkanediyl,                    R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;                            R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or            when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula—O—CH2—O—  (a-1),—O—CH2—CH2—O—  (a-2),—O—CH═CH—  (a-3),—O—CH2—CH2—  (a-4),—O—CH2—CH2—CH2—  (a-5), or—CH═CH—CH═CH—  (a-6);            R4 and R5 each independently are hydrogen, Ar1, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;    R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar2oxy;    R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, Ar1, Ar2C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl;    R10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;    R11 is hydrogen or C1-6alkyl;    Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo;    Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
WO-98/40383 and U.S. Pat. No. 6,187,786, which are incorporated herein in their entirety, disclose the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (VII)
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein    the dotted line represents an optional bond;    X is oxygen or sulfur;    -A- is a bivalent radical of formula
—CH═CH—(a-1),—CH2—CH2—(a-2),—CH2—CH2—CH2—(a-3),—CH2—O—(a-4),—CH2—CH2—O—(a-5),—CH2—S—(a-6),—CH2—CH2—S—(a-7),—CH═N—(a-8),—N═N—(a-9), or—CO—NH—(a-10);                wherein optionally one hydrogen atom may be replaced by C1-4alkyl or Ar1;            R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar2, Ar2—C1-6alkyl, Ar2-oxy, Ar2—C1-6alkyloxy; or when on adjacent positions R1 and R2 taken together may form a bivalent radical of formula—O—CH2—O—  (b-1),—O—CH2—CH2—O—  (b-2),—O—CH═CH—  (b-3),—O—CH2—CH2—  (b-4),—O—CH2—CH2—CH2—  (b-5), or—CH═CH—CH═CH—  (b-6);    R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar3-oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula—O—CH2—O—  (c-1),—O—CH2—CH2—O—  (c-2), or—CH═CH—CH═CH—  (c-3);    R5 is a radical of formula
                wherein R13 is hydrogen, halo, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;                    R14 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;                            R6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar5, Ar5—C1-6alkyloxyC1-6alkyl; or a radical of formula—O—R7  (e-1),—S—R7  (e-2),—N—R8R9  (e-3),            wherein R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar6, Ar6—C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR10 or -Alk-NR11R12;                    R8 is hydrogen, C1-6alkyl, Ar7 or Ar7—C1-6alkyl;            R9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar8, Ar8—C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar8-carbonyl, Ar8—C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino,            or a radical of formula -Alk-OR10 or -Alk-NR11R12;                        wherein Alk is C1-6alkanediyl;                    R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar9 or Ar9—C1-6alkyl;            R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar10 or Ar10—C1-6alkyl;            R12 is hydrogen, C1-6alkyl, Ar11 or Ar11—C1-6alkyl; and                        Ar1 to Ar11 are each independently selected from phenyl; or phenyl substituted with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.        
WO-98/49157 and U.S. Pat. No. 6,117,432, which are incorporated herein in their entirety, concern the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (VIII)
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein    the dotted line represents an optional bond;    X is oxygen or sulfur;    R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar1C1-6alkyl, Ar1oxy or Ar1C1-6alkyloxy;    R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar1 oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl or trihalomethoxy;    R5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar1, Ar1C1-6alkyloxyC1-6alkyl; or a radical of formula—O—R10  (a-1),—S—R10  (a-2),—N—R11R12  (a-3),            wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR13 or -Alk-NR14R15;                    R11 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;            R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar1carbonyl, Ar1C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical of formula -Alk-OR13 or -Alk-NR14R15;                            wherein Alk is C1-6alkanediyl;                                    R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar1C1-6alkyl;                    R14 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;                    R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or ArC1-6alkyl;                                                                                    R6 is a radical of formula
                wherein R16 is hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;                    R17 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;                            R7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;    R8 is hydrogen, C1-6alkyl or Ar2CH2 or Het1CH2;    R9 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; or    R8 and R9 taken together to form a bivalent radical of formula—CH═CH—  (c-1),—CH2—CH2—  (c-2),—CH2—CH2—CH2—  (c-3),—CH2—O—  (c-4), or—CH2—CH2—O—  (c-5);    Ar1 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;    Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl; and    Het1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
WO-00/39082 and U.S. Pat. No. 6,458,800, which are incorporated herein in their entirety, describe the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (IX)
or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein    ═X1—X2—X3- is a trivalent radical of formula
═N—CR6═CR7—(x-1),═N—N═CR6—(x-2),═N—NH—C(═O)—(x-3),═N—N═N—(x-4),═N—CR6═N—(x-5),═CR6—CR7═CR8—(x-6),═CR6—N═CR7—(x-7),═CR6—NH—C(═O)—(x-8), or═CR6—N═N—(x-9);                wherein each R6, R7 and R8 are independently hydrogen, C1-4alkyl, hydroxy, C1-4alkyloxy, aryloxy, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, cyano, amino, thio, C1-14alkylthio, arylthio or aryl;            >Y1—Y2- is a trivalent radical of formula>CH—CHR9—  (y-1),>C═N—  (y-2),>CH—NR9—  (y-3), or>C═CR9—  (y-4);            wherein each R9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC1-4alkyl, cyano, carboxyl, C1-4alkyl, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl, aryl;            r and s are each independently 0, 1, 2, 3, 4 or 5;    t is 0, 1, 2 or 3;    each R1 and R2 are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminocarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl; or    two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula—O—CH2—O—  (a-1),—O—CH2—CH2—O—  (a-2),—O═CH═CH—  (a-3),—O—CH2—CH2—  (a-4),—O—CH2—CH2—CH2—  (a-5), or—CH═CH—CH═CH—  (a-6);    R3 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, aryl, arylC1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl;    or a radical of formula—O—R10  (b-1)—S—R10  (b-2),—NR11R12  (b-3),    wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl, arylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR13 or -Alk-NR14R15;            R11 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;        R12 is hydrogen, C1-6alkyl, aryl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarbonylC1-6alkyl, arylC1-6alkyl, C1-6alkylcarbonylamino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl, C1-6alkyloxycarbonyl,                    C1-6alkyloxyC1-6alkylcarbonyl, mono- or di(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C1-13alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical of formula -Alk-OR13 or -Alk-NR14R15;                        wherein Alk is C1-6alkanediyl;                    R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl;            R14 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;            R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl;                            R4 is a radical of formula
    wherein R16 is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;            R16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R16 when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;        R17 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, arylC1-6alkyl, trifluoromethyl or di(C1-4alkyl)aminosulfonyl;            R5 is C1-6alkyl, C1-6alkyloxy or halo;    aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
In addition to the farnesyltransferase inhibitors of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) above, other farnesyltransferase inhibitors known in the art include: Argiabin (i.e. 1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide described in WO-98/28303 (NuOncology Labs); perrilyl alcohol described in WO-99/45912 (Wisconsin Genetics); SCH-66336, i.e. (+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide, described in U.S. Pat. No. 5,874,442 (Schering); L778123, i.e. 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, described in WO-00/01691 (Merck); compound 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone described in WO-94/10138 (Merck); and BMS 214662, i.e. (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile, described in WO 97/30992 (Bristol Myers Squibb); and Pfizer compounds (A) and (B) described in WO-00/12498 and WO-00/12499:

FLT3 kinase inhibitors known in the art include: AG1295 and AG1296; Lestaurtinib (also known as CEP 701, formerly KT-5555, Kyowa Hakko, licensed to Cephalon); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron Corp.); EB-10 and IMC-EB10 (ImClone Systems Inc.); GTP 14564 (Merk Biosciences UK). Midostaurin (also known as PKC 412 Novartis AG); MLN 608 (Millennium USA); MLN-518 (formerly CT53518, COR Therapeutics Inc., licensed to Millennium Pharmaceuticals Inc.); MLN-608 (Millennium Pharmaceuticals Inc.); SU-11248 (Pfizer USA); SU-11657 (Pfizer USA); SU-5416 and SU 5614; THRX-165724 (Theravance Inc.); AMI-10706 (Theravance Inc.); VX-528 and VX-680 (Vertex Pharmaceuticals USA, licensed to Novartis (Switzerland), Merck & Co USA); and XL 999 (Exelixis USA).
See also Levis, M., K. F. Tse, et al. (2001) “A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations.” Blood 98(3): 885-7; Tse K F, et al. (2001) Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia. Jul.; 15(7):1001-10; Smith, B. Douglas et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 2004; 103: 3669-3676; Griswold, Ian J. et al. Effects of MLN518, A Dual FLT3 and KIT Inhibitor, on Normal and Malignant Hematopoiesis. Blood, July 2004; [Epub ahead of print]; Yee, Kevin W. H. et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood, September 2002; 100: 2941-294; O'Farrell, Anne-Marie et al. SUI 1248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, May 2003; 101: 3597-3605; Stone, R. M. et al. PKC 412 FLT3 inhibitor therapy in AML: results of a phase II trial. Ann Hematol. 2004; 83 Suppl 1:S89-90; and Murata, K. et al. Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol. Chem. 2003 Aug. 29; 278(35):32892-8; Levis, Mark et al. Novel FLT3 tyrosine kinase inhibitors. Expert Opin. Investing. Drugs (2003) 12(12) 1951-1962; Levis, Mark et al. Small Molecule FLT3 Tyrosine Kinase Inhibitors. Current Pharmaceutical Design, 2004, 10, 1183-1193.